1. Field of the Invention
Milk fever (parturient paresis) is a hypocalcemic disorder associated with the onset of lactation in dairy cows. Hypocalcemia occurs because calcium (Ca) leaves the extracellular fluid pool to enter the mammary gland faster than it can be replaced by intestinal calcium absorption or bone calcium resorption. Milk fever can be prevented by measures that increase the rate of entry of calcium into the extracellular fluid compartment from intestine or bone.
2. Description of the Prior Art
Measures to increase the rate of calcium entry into the extracellular fluid include reduction of the calcium content [Goings, R. L. et al., "Prevention of parturient paresis by a prepartum, Ca-deficient diet", J. Dairy Sci., 57:1184 (1974); Jorgensen, N. A., "Combating milk fever", J. Dairy Sci., 57:933 (1974)] or the cation content of the prepartal diet [Block, E., "Manipulating dietary anions and cations for prepartum dairy cows to reduce incidence of milk fever", J. Dairy Sci , 67:2939 (1984); Goff, J. P. et al., "Addition of chloride to a prepartal diet high in cations increases 1,25-dihydroxyvitamin D response to hypocalcemia preventing milk fever", J. Dairy Sci. , 74:3863 (1991); Oetzel G. R., "Meta-analysis of nutritional risk factors for milk fever in dairy cattle", J. Dairy Sci. , 74:3900 (1991)], administration of parathyroid hormone [Goff, J. P. et al., "Effect of synthetic bovine parathyroid hormone in dairy cows: prevention of hypocalcemic parturient paresis", J. Dairy Sci., 69:2278 (1986)] and administration of vitamin D metabolites [Bar, A. et al., "Observation on the use of 1-.alpha.- hydroxyvitamin D.sub.3 in the prevention of bovine parturient paresis: the effect of a single injection on plasma 1-.alpha.-hydroxyvitamin D.sub.3, 1,25-dihydroxyvitamin D.sub.3, Ca, and hydroxyproline", J. Dairy Sci., 68:1952 (1985); Goff, J. P. et al., "Effect of subcutaneously released 24F-1,25-dihydroxyvitamin D.sub.3 on incidence of parturient paresis in dairy cows", J. Dairy Sci., 73:406 (1990); Hoffsis, G. F. et al. "The use of 1,25-.dihydroxycholecalciferol in the prevention of parturient hypocalcemia in dairy cows", Bovine Pract., 13:88 (1979)]. Oral administration of CaCl.sub.2 in aqueous and gel forms at parturition as a preventive of milk fever in dairy cattle has also been attempted with varying success [Hallgren, W., "Studies on parturient paresis in dairy cows", Nord Veterinaermed., 7:433 (1955); Jonsson, G. et al., "Trials witch prophylactic treatment of parturient paresis", Vet. Rec., 87:575 (1970); Oetzel, G. R., "Effects of prophylactic treatment with a calcium chloride gel on serum calcium concentration at calving, milk fever, and displaced abomasum in Holstein cows", J. Dairy Sci , 76 (supplement): 304 (1993); Queen W. G. et al., "Effects of oral administration of a Ca containing gel on serum Ca concentration in postparturient dairy cows", J. Am. Vet. Med. Assoc., 202:607 (1993); Ringarp, N. et al., "The prophylaxis of milk fever in cattle by oral administration of Ca chloride gel", Zentralbl. Veterinaermed. Reihe A 14:242 (1967)]. Most commercially available CaCl.sub.2 products are packaged in tubes containing about 50 g of calcium. Anecdotes suggest that cows often are treated with more than one tube to prevent milk fever or relapses to milk fever. Ample evidence exists to suggest that this treatment results in an increase in blood calcium levels for at least 4 to 6 h [Goff, J. P. et al., "Oral administration of Ca salts for treatment of hypocalcemia in cattle", J. Dairy Sci., 76:101 (1993); Queen et al., supra], however, this treatment is not without risk. Calcium chloride is very irritating. Should abrasions exist in the cow's mouth prior to treatment, the CaCl.sub.2 might irritate the exposed submucosa to the point of ulceration. Also, calcium chloride rapidly induces a metabolic acidosis in treated animals, as evidenced by the reduction in both blood and urine pH. Chloride is a fixed (non-metabolizable) anion that is readily absorbed into the blood. Blood pH decreases to maintain electroneutrality of the blood [Stewart, P. A., "Modern quantitative acid-base chemistry", Can. J. Physiol. Pharmacol., 61:1444 (1983)]
Recently, Goff et al. [J. Dairy Sci. 76:101 (1993)], supra, established that concentrated CaCl.sub.2 solutions are absorbed with greater efficiency than are dilute CaCl.sub.2 solutions when administered as a drench (using increased blood calcium concentration as an indicator) and that CaCl.sub.2 in solution is absorbed with greater efficiency than is CaCl.sub.2 suspended in a commercial paste. Calcium chloride increased blood calcium concentrations more quickly than did calcium propionate, but calcium propionate effects lasted longer. The CaCO.sub.3 drenches were ineffective. Drenching with CaCl.sub.2 solutions increased blood calcium to a greater extent than did placing the solution into the rumen via stomach tube. However, a risk of aspiration of liquid drenches in hypocalcemic animals with reduced epiglottal reflex exists, making the development of a paste formulation advantageous in some circumstances. Goff et al. [J. Dairy Sci. 76:101 (1993)], supra, also reported that clinical metabolic acidosis had occurred in a cow treated with 100 g of calcium as CaCl.sub.2 at calving and again at 12 h postcalving.
Preparations of calcium propionate do not induce a metabolic acidosis in treated cattle and are nearly as effective at raising plasma calcium concentration as CaCl.sub.2 preparations. In addition, the gluconeogenic properties of propionate may be useful in reducing the incidence of ketosis and fatty liver.
Calcium-containing commercial gels can be made from water-soluble (such as propylene glycol) and water-insoluble carriers (such as vegetable oils). The oils tend to be less expensive and may be more palatable; however, studies indicate that oil-based carriers appear to decrease the availability of the calcium for absorption. It seems likely that insoluble calcium soaps are formed. On the other hand, propylene glycol can be used to form a gel that is fairly readily soluble in water and that will also serve as an energy source for the cow.
Though calcium propionate formulations demonstrate promise in terms of long-lasting physiological effects, they possess certain inherent problems related to administration. When formulated with propylene glycol into pastes, the resultant compositions tend to set into unmanageable hardened masses which are difficult to eject from tubes. Also, calcium absorption is not as rapid as when it is administered as the chloride salt. In extreme cases of hypocalcemia, the slower absorption rate could impede recovery of the animal.